1. Field of the Invention
The invention relates to compositions of multivesicular liposomes useful as a drug delivery system and processes for their manufacture.
2. Description of Related Art
Optimal treatment with many drugs requires maintenance of a drug level for an extended period of time. For example, optimal anti-cancer treatment with cell cycle-specific antimetabolites requires maintenance of a cytotoxic drug level for a prolonged period of time. The half-life of many drugs after an intravenous (IV), subcutaneous (SC), intraperitoneal (IP), intraarterial (IA), intramuscular (IM), intrathecal (IT), or epidural dose is very short, being in the range of a fraction of an hour to a few hours. Cytarabine is a highly schedule-dependent anti-cancer drug. Because this drug kills cells only when they are making DNA, prolonged exposure at therapeutic concentration of the drug is required for optimal cell kill. To achieve optimal cancer cell kill with a cell cycle phase-specific drug like cytarabine, two major requirements need to be met: irreversible harm to the host; and second, the tumor must be exposed for a sufficient length of time so that all or most of the cancer cells have attempted to synthesize DNA in the presence of cytarabine.
An example of another class of drugs that are schedule-dependent is the class of aminoglycoside antibiotics. For instance, amikacin is an aminoglycoside antibiotic that has clinically significant activity against strains of both gram negative and gram positive bacteria, but has a serum half-life of about two to three hours. Yet in current practice, the drug is normally administered by intravenous or intramuscular routes once or twice a day. The most commonly used clinical dose is 15 mg/Kg/day, which is equivalent to a maximum recommended daily dose of 1 g per day.
For infections such as those confined to a local region of soft tissue or bone, an implantable drug depot with sustained release properties would be advantageous, both to increase local levels of the drug in the affected tissue and to reduce or avoid the systemic toxicity of the free drug.
Thus, new and better methods for sustained release delivery of drugs in the treatment of disease are needed. The present invention meets this need by providing compositions of multivesicular liposomes useful as a sustained release drug delivery system and a process for their manufacture.
Multivesicular liposomes (MVL), first reported by Kim, et al. (Biochim, Biophys. Acta, 728:339-348, 1983), are uniquely different from other lipid-based drug delivery systems such as unilamellar (Huang, Biochemistry, 8:334-352, 1969; Kim, et al., Biochim. Biophys. Acta, 646:1-10, 1981) and multilamellar (Bangham, et al., J Mol. Bio., 13:238-252, 1965) liposomes. The main structural difference is that in contrast to unilamellar liposomes (also known as unilamellar vesicles, or "ULV"), multivesicular liposomes (MVL) contain multiple aqueous chambers per particle. In contrast to multilamellar liposomes (also known as multilamellar vesicles or "MLV"), the multiple aqueous chambers in multivesicular liposomes are non-concentric. The structural differences between unilamellar, multilamellar, and multivesicular liposomes are illustrated in FIG. 1.
Because of the similarity in acronyms, multivesicular liposomes (MVL) are frequently confused with multilamellar liposomes (MLV). Nevertheless, the two entities are entirely distinct from each other. The structural and functional characteristics of MVL are not directly predictable from current knowledge of ULV and MLV. As described in the book edited by Jean R. Philippot and Francis Schuber (Liposomes as Tools in Basic Research and Industry, CRC press, Boca Raton, Fla.,1995, page 19), MVL are bounded by an external bilayer membrane shell, but have a very distinctive internal morphology, which may arise as a result of the special method employed in the manufacture. Topologically, multivesicular liposomes (MVL) are defined as liposomes containing multiple non-concentric chambers within each liposome particle, resembling a "foam-like" matrix; whereas multilamellar vesicles (MLV) contain multiple concentric chambers within each liposome particle, resembling the "layers of an onion".
The presence of internal membranes distributed as a network throughout MVL may serve to confer increased mechanical strength to the vesicle, while still maintaining a high volume:lipid ratio compared with MLV. The multivesicular nature of MVL also indicates that, unlike for ULV, a single breach in the external membrane of a MVL will not result in total release of the internal aqueous contents. Thus, both structurally and functionally the MVL are unusual, novel and distinct from all other types of liposomes. As a result, the functional properties of MVL are not predictable based on the prior art related to conventional liposomes such as ULV and MLV.
The prior art describes a number of techniques for producing ULV and MLV (for example, U.S. Pat. Nos. 4,522,803 to Lenk; 4,310,506 to Baldeschwieler; 4,235,871 to Papahadjopoulos; 4,224,179 to Schneider; 4,078,052 to Papahadjopoulos; 4,394,372 to Taylor; 4,308,166 to Marchetti; 4,485,054 to Mezei; and 4,508,703 to Redziniak). The prior art also describes methods for producing MVL (Kim, et al., Biochim. Biophys. Acta, 728:339-348, 1983). For a comprehensive review of various methods of ULV and MLV preparation, refer to Szoka, et al., Ann. Rev. Biophys. Bioeng.,9:465-508, 1980.
In the method of Kim, et al. (Biochim. Biophys. Acta, 728:339-348, 1983), the pharmaceutical utility of MVL encapsulating small therapeutic molecules, such as cytosine arabinoside or cytarabine, is limited. Subsequent studies (Kim, et al., Cancer Treat. Rep., 71:705-711, 1987) showed that the release rate of encapsulated molecules into biological fluids can be modulated by encapsulating in the presence of a hydrochloride.
Heretofore, control of the release rate of a biologically active substance from multivesicular liposomes could only be achieved by use of hydrohalides. For a drug-delivery system, it is highly advantageous to be capable of controlling the release rate for encapsulated substances through release rate modifying agents used during manufacture of the liposomes, and to have a wide choice of these release-rate modifying agents.
Accordingly, it is an object of the present invention to provide a controlled release depot preparation of multivesicular liposomes which provides a sustained exposure of a biologically active substance at a therapeutic concentration.
It is a further object of the present invention to provide a method of preparing such depot preparations.
Other and further objects, features, and advantages of the invention are inherent therein and appear throughout the specification and claims.